Abstract Introduction Regulatory T cell (Treg) therapy faces clinical challenges related to a lack of persistence, stability, homing and scalability. Improvements often address singular issues and fail to engender ‘repair-ready’ cells. Methods We developed GNTI-823, an engineering strategy to generate Tregs (EngTreg) from human CD4 T cells that constitutively express FOXP3 for stability and scalability; contain a rapamycin-activated chemically induced IL-2 signaling complex (CISC) for persistence; and express the IL-33-responsive alarmin receptor ST2 for inflammatory-homing and in vivo functionality. Results ST2 expression successfully conferred a ‘Tissue’ Treg phenotype, characterized by high expression of inflammatory homing receptors, metabolic genes and tolerogenic factors absent from non-ST2 EngTregs or circulating Tregs. Indeed, in a model of ischemic stroke, ST2-EngTreg cells demonstrated preferential homing and improved sensorimotor, learning and memory outcomes. in vitro, ST2-EngTregs sequestered higher amounts per cell of inflammatory factors, IL-33, TNF and IL2 that limit macrophage/microglial and T cell activation. Lastly, ST2-EngTregs remained stable and persisted under prolonged inflammatory and IL-2 scarce conditions. Conclusion Thus, GNTI-823 EngTregs are designed to home, function and persist in neuroinflammatory sites, which show pre-clinical promise for the treatment of ischemic stroke and other neuroinflammatory and degenerative conditions. Funding Source NIH SBIR Topic Categories Translational and Interventional Immunology (TI)
Zammit et al. (Tue,) studied this question.